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CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: three cases

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, such as ipilimumab, have generated measurable immune responses to Melan-A, NY-ESO-1, and gp100 antigens in metastatic melanoma. Vaccination against such targets has potential for immunogenicity and may produce an effector-memory T-cell response.

Methods

To determine the effect of CTLA-4 blockade on antigen-specific responses following vaccination, in-depth immune monitoring was performed on three ipilimumab-treated patients prevaccinated with gp100 DNA (IMF-24), gp100209–217 and tyrosinase peptides plus GM-CSF DNA (IMF-32), or NY-ESO-1 protein plus imiquimod (IMF-11); peripheral blood mononuclear cells were analyzed by tetramer and/or intracellular cytokine staining following 10-day culture with HLA-A*0201-restricted gp100209–217 (ITDQVPFSV), tyrosinase369–377 (YMDGTMSQV), or 20-mer NY-ESO-1 overlapping peptides, respectively. Tumors from IMF-32 were analyzed by immunohistochemistry to help elucidate mechanism(s) underlying tumor escape.

Results

Following vaccination, patients generated weak to no CD4+ or CD8+ T-cell response specific to the vaccine antigen but demonstrated increases in effector-memory (CCR7loCD45RAlo) tetramer+CD8+ T cells. After ipilimumab induction, patients experienced a robust, although sometimes transient, antigen-specific response for gp100 (IMF-32 and IMF-24) or NY-ESO-1 (IMF-11) and produced polyfunctional intracellular cytokines. Primary and metastatic tumors expressed tyrosinase but not gp100 or class I/II MHC molecules.

Conclusion

Vaccination induced a measurable antigen-specific T-cell response that increased following CTLA-4 blockade, potentially “boosting” the vaccine-primed response. Tumor escape may be related to antigen loss or lack of MHC expression necessary for immune activity. These results in a limited number of patients support the need for further research into combining vaccination with ipilimumab and provide insight into mechanisms underlying tumor escape.

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Abbreviations

ALC:

Absolute lymphocyte count

CTLA-4:

Cytotoxic T-lymphocyte antigen-4

GM-CSF:

Granulocyte macrophage colony-stimulating factor

H&E:

Hematoxylin and eosin

ICOS:

Inducible co-stimulator

ICS:

Intracellular cytokine staining

IHC:

Immunohistochemistry

PBMC:

Peripheral blood mononuclear cell

WBC:

White blood cell

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Acknowledgments

We thank Dr. Immanuel Luescher from Tetramer Core, Lausanne Branch, Ludwig Institute of Cancer Research, for providing the tetramers; Cora Mariano from the MSKCC Departments of Pathology for the collection of tumor tissues; and Hematology for the lymphocyte counts. This work was supported by Swim Across America, the Experimental Therapeutics Center of MSKCC and Ludwig Foundation. JDW was supported by a Damon Runyon-Lilly Clinical Investigator Award. JY was supported by MSKCC Pilot Grant of Grant number P50AT002779 from the National Center for complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS). Editorial and writing assistance was provided by StemScientific with funding from Bristol-Myers Squibb Company.

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Authors and Affiliations

  1. Immunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute, New York, NY, 10065, USA

    Jianda Yuan, Brian Ginsberg, Teresa Rasalan, Humilidad F. Gallardo, Yinyan Xu, James P. Allison & Jedd D. Wolchok

  2. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 340, New York, NY, 10065, USA

    David Page, Yanyun Li & Jedd D. Wolchok

  3. Department of Medicine, New York University Cancer Institute, NYU Langone Medical Center, New York, NY, 10016, USA

    Sylvia Adams & Nina Bhardwaj

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Klaus Busam

  5. Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Lloyd J. Old & Achim Jungbluth

Authors
  1. Jianda Yuan
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  2. Brian Ginsberg
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  14. Jedd D. Wolchok
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Corresponding author

Correspondence to Jedd D. Wolchok.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Tenth International Conference on Progress in Vaccination against Cancer (PIVAC 10), held in St. Catharine’s College, Cambridge, UK, September 27th–30th, 2010. It is part of a CII series of Focussed Research Reviews and meeting report.

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Yuan, J., Ginsberg, B., Page, D. et al. CTLA-4 blockade increases antigen-specific CD8+ T cells in prevaccinated patients with melanoma: three cases. Cancer Immunol Immunother 60, 1137–1146 (2011). https://doi.org/10.1007/s00262-011-1011-9

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